Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Gender medicine and oncology: report and consensus of an ESMO workshop.

BACKGROUND: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. DESIGN: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. RESULTS: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. CONCLUSION: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.

Predicting decline of kidney function in lupus nephritis using urine biomarkers.

OBJECTIVE: To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). METHODS: At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. RESULTS: All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). CONCLUSION: The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.

Simulation-based study comparing multiple imputation methods for non-monotone missing ordinal data in longitudinal settings.

The application of multiple imputation (MI) techniques as a preliminary step to handle missing values in data analysis is well established. The MI method can be classified into two broad classes, the joint modeling and the fully conditional specification approaches. Their relative performance for the longitudinal ordinal data setting under the missing at random (MAR) assumption is not well documented. This article intends to fill this gap by conducting a large simulation study on the estimation of the parameters of a longitudinal proportional odds model. The two MI methods are also illustrated in quality of life data from a cancer clinical trial.

Longitudinal quality of life data: a comparison of continuous and ordinal approaches.

PURPOSE: In cancer clinical trials, health-related quality of life (HRQoL) is a major outcome measure. It is generally assessed at specified time intervals by filling out a questionnaire with ordered response categories. Despite recent advances in the statistical methodology for handling ordinal longitudinal outcome data, most users keep treating HRQoL scales as continuous rather than ordinal variables regardless of the number of categories. The purpose of this study was to compare the results of analyzing HRQoL longitudinal data under both approaches, continuous and ordinal. METHODS: The EORTC QLQ-C30 scores of two EORTC randomized brain cancer clinical trials (26951 and 26981) were analyzed using the two approaches. In the 26951 trial, a total of 368 patients were randomly assigned to receive either radiotherapy (RT) or the same RT plus procarbazine, CCNU, and vincristine. In the 26981 trial, 573 patients were randomly allocated to RT or RT plus temozolomide. Comparison of the two treatment arms was done using methods for longitudinal quantitative and longitudinal ordinal data. Both statistical methods were adapted to account for missing data and compared in terms of statistical significance of the results (p values) but also with respect to data interpretation. RESULTS: Three scales, i.e., appetite loss, insomnia, and drowsiness, presenting four response categories ("Not at all", "A little", "Quite a bite", and "Very much") were analyzed in each trial. Both statistical methods (continuous and ordinal) showed statistically significant differences between the two treatments, not only globally but also at the same assessment time points. The magnitude of the p values, however, varied at some time points and was less pronounced in the ordinal approach. CONCLUSIONS: The analysis of the two clinical trials showed that treating the HRQoL scales by a quantitative or an ordinal method did not make much difference as far as statistical significance was concerned. The interpretation of results, however, was easier under the ordinal approach. Treatment effects may be more meaningful when expressed in terms of odds ratios than as mean values, particularly when the number categories is small.

Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).

BACKGROUND: This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. METHODS: This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( ± resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. RESULTS: The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2-73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1-70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42-0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7-22.1) and 9.9 months (95% CI 9.3-13.7), respectively. CONCLUSIONS: This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain.

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel.

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

The relationship of retinal vessel diameter to changes in diabetic nephropathy structural variables in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. METHODS: Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. RESULTS: While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [Vv((Int/cortex))] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. CONCLUSIONS/INTERPRETATION: Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv((Int/cortex),) a measure of interstitial expansion in persons with type 1 diabetes mellitus.

Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323).

BACKGROUND: The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients' health-related quality of life (HRQOL) and symptoms was investigated. METHODS: HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol. RESULTS: Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent. CONCLUSION: Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner.

The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?

Initial studies showing an approximately 80% rate of progression from microalbuminuria (MA) to proteinuria in type 1 diabetic patients led to the broad acceptance of MA as a useful clinical predictor of increased diabetic nephropathy (DN) risk. Some MA patients, however, have quite advanced renal structural changes, and MA may, in these cases, be a marker rather than a predictor of DN. More recent studies have observed only about a 30-45% risk of progression of MA to proteinuria over 10 years, while about 30% of type 1 diabetic patients with MA became normoalbuminuric and the rest remained microalbuminuric. The finding that some MA patients have only mild diabetic renal lesions is consistent with the lower than originally estimated risk of progression from MA to proteinuria and with the notion that some MA patients revert to normoalbuminuria. To increase the complexity of the scenario, some normoalbuminuric long-standing type 1 diabetic patients have well-established DN lesions and approximately 40% of all patients destined to progress to proteinuria are normoalbuminuric at initial screening, despite many years of diabetes. A similar picture is emerging in type 2 diabetic patients, although fewer studies have been conducted. Thus, the predictive precision for MA to progress to overt nephropathy over the subsequent decade or so is considerably less than originally described. It is unclear whether this is due to changes in the natural history of DN resulting from improved glycemia and blood pressure control, or whether there were overestimates of risk in the original studies due to the small sample sizes, post hoc analyses, and variable MA definitions. Albumin excretion rate (AER) remains the best available noninvasive predictor of DN risk and should be regularly measured according to established guidelines. However, AER may be unable to define patients who are safe from or at risk of DN with an accuracy that is adequate for optimal clinical decision making or for the design of certain clinical trials. Investigations into new risk markers or into the combined use of several currently available predictive parameters are needed.

Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria.

Although microalbuminuria is known to foretell the later development of overt proteinuria in patients with insulin-dependent diabetes mellitus (IDDM), different investigators have reported different levels of albuminuria as being predictive. However, whether different levels of albuminuria reflect differences in glomerular structure is not well known. In this study, we divided a cohort of 66 nonproteinuric long-standing (duration 20 +/- 7 years) IDDM patients, who had both renal functional and structural studies performed, into four groups according to their urinary albumin excretion rate (AER). The several different levels of microalbuminuria previously reported to be predictive served to demarcate these groups: group I, AER < or = 22 mg/24 h (upper limit for normal in our laboratory) (33 patients); group II, AER 23-45 mg/24 h (11 patients); group III, AER 46-100 mg/24 h (13 patients); and group IV, AER 101-220 mg/24 h (9 patients). Creatinine clearance was similar in groups I, II, and III but was lower in group IV. Systemic hypertension was present in five patients in group I, one in group II, seven in group III, and five in group IV. Mean values for glomerular basement membrane (GBM) width and volume fraction of the mesangium [Vv(mes/glom)] were greater in all groups than in a group of 52 age-matched normal kidney donors (P < 0.0001). Also, filtration surface density [Sv(PGBM)], inversely related to Vv(mes/glom) (r = 0.61, P < 0.0001), was reduced in all diabetic groups compared with the normal group (P < 0.0001). Structural measures were identical in group I and II.(ABSTRACT TRUNCATED AT 250 WORDS)

Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.

Only a minority of patients with type 1 diabetes develop diabetic nephropathy (DN). Poor glycemic control cannot fully explain DN risk, and family studies suggest genetic susceptibility factors. To understand familial DN concordance, we evaluated glomerular structure in families with type 1 diabetic sibling pairs. Kidney function and biopsy studies were performed in 21 probands (P) (first to develop diabetes) and 21 siblings (S) (second to develop diabetes), most with normal urinary albumin excretion rates (UAER). Glomerular structure was measured by morphometry. Intrafamilial correlation was estimated by one-way random-effects ANOVA and by mixed-effects ANOVA, adjusting for age and duration of diabetes. Diabetes duration was, by definition, longer in P than in S, while age and sex were similar. HbA1c over 5 years and blood pressure were not different in P and S and were without familial effect. UAER was greater in P than in S (P < 0.05), with strong familial effect (P = 0.03). A strong concordance among siblings for mesangial fractional volume (P < or = 0.01) remained significant after adjustment for diabetes duration and age (P = 0.04). Results were similar for mesangial cell (P = 0.01; adjusted P = 0.04) and mesangial matrix fractional volumes (P < 0.01; adjusted P = 0.06). There was also clustering of the patterns of glomerular lesions. For example, if P had relatively marked glomerular basement membrane thickening compared with mesangial matrix expansion, S had a similar pattern (chi2, P < 0.025). Strong concordance in severity and patterns of glomerular lesions in type 1 diabetic siblings, despite lack of concordance in glycemia, supports an important role for genetic factors in DN risk.

Skeletal muscle basement membrane in maturity-onset diabetes in the young.

We have studied skeletal muscle capillary basement membrane width (CBMW) and intensity of skeletal muscle extracellular basement membrane staining for albumin and IgG in eight families with maturity-onset diabetes in the young (MODY). Ninety-two MODY patients were identified. Sixty-three of these patients, 33 relatives with nondiagnostic oral glucose tolerance studies, and 61 normoglycemic relatives were studied for glucose and insulin. Twenty-six of these MODY patients, 20 normoglycemic relatives, and 16 unrelated normal controls had skeletal muscle capillary morphologic studies. The muscle capillary basement membrane was significantly increased in MODY patients younger than 40 yr when compared with unrelated normal subjects and relatives of the same age (P less than 0.001). However, in these families, the CBMW of MODY patients showed no significant thickening with age (slope = 0.45, P less than 0.14), as expected and seen in the normal subjects and in the normoglycemic relatives of the patients (slope = 1.21, P less than 0.001). The slope derived from the linear regression of age and CBMW in MODY patients (0.45 +/- 0.29) was significantly less (P less than 0.05) than that of the nondiabetic subjects (1.21 +/- 0.19). The mean intensity of skeletal muscle extracellular basement membrane staining for albumin was higher in MODY patients (1.1 +/- 0.15) than in unrelated normal subjects (0.7 +/- 0.1, P less than 0.025) and normal MODY family members (0.6 +/- 0.08, P less than 0.01). The unexpected absence of basement membrane thickening with age in the MODY patients may explain the paucity of vascular complications that have been reported by some.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis.

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

The regulation of total body fat: lessons learned from lipectomy studies.

Surgical removal of body fat (partial lipectomy) is a means of directly reducing fat such that metabolic and behavioral responses can be readily attributed to the lipid deficit. If total body fat is regulated, then lipectomy should trigger compensatory increases in nonexcised white adipose tissue (WAT) mass and/or regrowth at excision sites. Many species, including laboratory rats and mice, show lipectomy-induced compensatory recovery of body fat. Those animals exhibiting naturally occurring annual adiposity cycles, such as ground squirrels and hamsters, do so most impressively reaching seasonally appropriate body fat levels indistinguishable from controls. Reparation of the lipid deficit occurs without an increase in food intake, and generally through enlargement of non-excised WAT mass, rather than regrowth of excised WAT. A body fat regulatory system involving humoral and sensory neural inputs to the brain as well as sympathetic neural outputs from brain to adipose tissue is presented. Collectively, the lipectomy model appears useful for testing mechanisms controlling adiposity, or individual depot growth, and offers insight into how lipid stores fluctuate naturally.

B cell ontogeny in rabbits. Immunofluoresecent localization of B cells in fetal and neonatal rabbits.

The mammalian equivalent of the Bursa of Fabricius, the organ responsible for B cell maturation in avian species, has not been identified despite anatomic and ablative studies which suggest that the gut-associated lymphoid tissues (GALT) subserve this function. By analogy to the Bursa, the mammalian organ directing B cell ontogeny should be the site where IgM-bearing cells (B cells) are first identifiable. In this study, fluorescein-tagged heavy chain specific antirabbit IgM is used to localize initial sites of B cell appearance in rabbit fetal and neonatal lymphoid tissues. IgM-bearing cells are found 2 days before birth in the thymus and 1 day before birth in GALT. Immunoglobulin-bearing cells in spleen, lymph node, and bone marrow are undetectable until after birth. B cells bearing the IgM marked precede the appearance of IgG-bearing cells by 1 to 4 days in all instances. Intraperitoneal implantation of Millipore chambers containing immature fetal thymic tissue into neonatal hosts reveals that in situ development of IgM cells takes place independent of host cell traffic. The results suggest that B cell ontogeny in mammals is more complex than in avian species and demonstrates probable involvement of the thymus in the maturational process.

Pediatric renal transplants--results with sequential immunosuppression.

Cyclosporine has improved the results of renal transplantation. In 1984, we began using it as part of a sequential immunosuppression protocol (MALG, AZA, P, and delayed administration of CsA) in our pediatric renal transplant recipients. We studied the outcome of the 131 pediatric renal transplants (less than or equal to 18 years of age at transplant) performed at our institution between June 1984 and March 1991. We compared these results with the 144 similar transplants performed since January 1980 that did not involve CsA immunosuppression. In the sequential immunosuppression group, there were 97 primary (74%) (26 [27%] cadaver, 71 [73%] living donor [LD]) and 34 (26%) retransplant (23 [68%] CAD, 11 [32%]) recipients. Age at transplant (mean +/- SD) was 7.4 +/- 5.5. Overall, 1-year actuarial graft survival was 93%; 1-year patient survival was 100%. The mean number of hospital readmissions was 3.0 +/- 3.5; 26 (20%) were readmission-free. The mean number of rejection episodes was .87 +/- 1.3 per patient; 73 (56%) were rejection-free. Importantly, LD (vs. CAD) recipients had fewer rejection episodes (P = 0.06). In the first post-transplant year, the serum creatinine level was significantly lower in primary (vs. retransplant) recipients and in LD (vs. CAD) recipients (P less than 0.05). In the 144 patients not receiving CsA, there were 129 (90%) primary (27 CAD, 102 LD) and 15 (10%) retransplant (7 CAD, 8 LD) recipients. Age at transplant was 6.9 +/- 5.3 years. The 1-year actuarial graft survival rate was 82%; the 1-year patient survival rate was 94%. The mean number of hospital readmissions was 3.3 +/- 2.3; 5 (8%) were readmission-free. The mean number of rejection episodes was 1.2 +/- 1.5; 27 (45%) were rejection-free. There was no difference in the serum creatinine level based on donor source or transplant number. Sequential immunosuppression has significantly improved patient (P = 0.003) and graft survival (P = 0.004) rates. Comparing sequential vs. non-CsA immunosuppression, there was no difference in the number of readmissions (P = 0.47), number of rejection episodes (P = 0.17), or serum creatinine level. The number of rejection-free patients was significantly lower in LD (vs. CAD) recipients (P less than 0.05). There was no evidence of progressive deterioration in renal function in the sequential (vs. non-CsA) recipients.

Effects of chronic exercise on blood volume expansion and hematologic indices during pregnancy.

OBJECTIVE: To compare blood volumes and hematologic indices between nine aerobically trained, physically active pregnant women who continued to exercise throughout gestation and five healthy yet sedentary gravidas. METHODS: Subjects were tested on three occasions: 25 and 36 weeks of pregnancy and 12 weeks postpartum. Plasma volumes were estimated by dye dilution with Evans blue. Blood samples were taken from the antecubital vein with the subjects resting in a seated, semirecumbent position. In addition to plasma volume estimations, blood samples were analyzed for hematocrit ratio, hemoglobin concentration, red cell count, and plasma protein concentration. Blood volumes and red cell volumes were calculated from plasma volume estimates and hematocrit ratios. RESULTS: Average birth weight and length of gestation did not differ between the subject groups. Analysis of variance indicated that absolute blood volume measures were significantly greater (P < .01) in the physically active compared to sedentary subjects at all three test times. Similar results were found for plasma and red cell volumes (P < .01). Blood volumes relative to body weight were significantly higher in physically active subjects (P < .01) than in their sedentary counterparts at 25 weeks (88.5 versus 75.5 mL/kg) and at 36 weeks (88.4 versus 70.9 mL/kg), as well as at 12 weeks postpartum (72.2 versus 57.6 mL/kg). All vascular volumes were significantly (P < .001) lower at 12 weeks postpartum compared to those seen during pregnancy in both subject groups. Hematologic indices of hematocrit ratio, hemoglobin concentration, red cell count, and plasma protein concentration were all greater (P < .001) at 12 weeks postpartum than during pregnancy. CONCLUSIONS: Physically active women possessed significantly greater vascular volumes than their sedentary counterparts. Although this difference was maintained throughout gestation as the active gravidas continued to exercise, there was no apparent effect on pregnancy outcome.

Diabetic nephropathy as a model for the use of renal structural endpoints in clinical trials.

Slowly developing renal diseases (SDRD) such as diabetic nephropathy (DN) and hypertensive nephrosclerosis constitute the large majority of disorders leading to end-stage renal disease (ESRD). These disorders are characterized by years to decades without renal functional abnormalities during which renal structural changes are developing. The earliest renal functional abnormalities [such as microalbuminuria in patients with insulin dependent diabetes mellitus (IDDM)] are often associated with already well established renal lesions that may progress independent of the initiating cause. Since the clinical manifestations of these disorders are dependent upon established structural changes, prevention of the early lesions seems a logical goal and thus a useful endpoint for clinical trials. Functional endpoints are impractical at these early stages as they would take too long to manifest. Diabetic nephropathy in IDDM patients is a useful model for such study design, since there is sufficient knowledge of the natural history of the disorder and of the important structural endpoints to allow for the statistical power calculations crucial for study design. More information regarding natural history and structural-functional relationships is needed in non-insulin dependent diabetes, hypertension, and other SDRD before intervention trials using renal structural endpoints can be developed for these important causes of ESRD.

Assessment of structure and function in progressive renal disease.

The incidence and prevalence rates of end-stage renal disease (ESRD) in the United States continue to increase. In 1995, the incidence rate was 262 per million population, with a point prevalence rate of 975 per million population. The exact number of individuals with abnormal renal function but not yet at end stage is difficult to assess. Crude estimates suggest that approximately 0.4% of the U.S. population has serum creatinine values greater than 2.0 mg/dl. In some sub-populations, such as African Americans, the estimate is + as high as 1.0%. The rate of progression, likewise, is difficult to assess. In general, renal manifestations of certain systemic diseases such as diabetes mellitus and systemic lupus erythematosus, and those with significant proteinuria (usually greater that 3.0 g/24 hr) seem to have a more rapid progressive course to end stage. If intervention is expected to be successful in halting or slowing down progression, accurate assessment of the early manifestations of renal disease, structure, and function need to be established. Currently accepted methods of assessment of renal disease include measurement of renal function such as serum creatinine and glomerular filtration rate, measurement of proteinuria, assessment of tubular function, glomerular sieving and permselectivity, radiologic imaging techniques, and evaluation of histo-morphometry. Interventions that have been shown to slow progression include control of hypertension, and treatment modalities that reduce proteinuria, such as, the use of angiotensin converting enzyme inhibitors. Further clinical and basic science studies are needed to accurately define the important predictors of progression, and interventions that are effective in slowing or halting progression.